Intracellular pathways of pancreatic β‐cell apoptosis in type 1 diabetes

Thomas, Helen E.; Kay, Thomas W. H.

doi:10.1002/dmrr.1253

Cited by 21 publications

(20 citation statements)

References 75 publications

(86 reference statements)

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“…The serine/threonine kinase receptor-interacting protein 1 (RIP1) is another initiator of necrotic cell death that is induced by ligand-receptor interactions. ATP depletion plays a crucial role as an initiating factor in this process(20; 21). Other factors including the lyososmal enzyme acid-sphingomyelinase, cytosolic phospholipase A(2) and calpains, a Ca 2 -dependent cysteine protease family, all of which contribute to cell membrane destabilization.…”

Section: Mechanisms Of β Cell Death In T1dmentioning

confidence: 99%

Life and death of β cells in Type 1 diabetes: A comprehensive review

Wilcox

Rui

Hebrok

et al. 2016

Journal of Autoimmunity

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Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic β cells. Immune modulators have achieved some success in modifying the course of disease progression in T1D. However, there are parallel declines in C-peptide levels in treated and control groups after initial responses. In this review, we discuss mechanisms of β cell death in T1D that involve necrosis and apoptosis. New technologies are being developed to enable visualization of insulitis and β cell mass involving positron emission transmission that identifies β cell ligands and magnetic resonance imaging that can identify vascular leakage. Molecular signatures that identify β cell derived insulin DNA that is released from dying cells have been described and applied to clinical settings. We also consider changes in β cells that occur during disease progression including the induction of DNA methyltransferases that may affect the function and differentiation of β cells. Our findings from newer data suggest that the model of chronic long standing β cell killing should be reconsidered. These studies indicate that the pathophysiology is accelerated in the peridiagnosis period and manifest by increased rates of β cell killing and insulin secretory impairments over a shorter period than previously thought. Finally, we consider cellular explanations to account for the ongoing loss of insulin production despite continued immune therapy that may identify potential targets for treatment. The progressive decline in β cell function raises the question as to whether β cell failure that is independent of immune attack may be involved.

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Section: Mechanisms Of β Cell Death In T1dmentioning

confidence: 99%

Life and death of β cells in Type 1 diabetes: A comprehensive review

Wilcox

Rui

Hebrok

et al. 2016

Journal of Autoimmunity

View full text Add to dashboard Cite

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“…Pancreatic b cells surrounded by inflammatory infiltrate are exposed to multiple cell stress mediators, hyperglycemia, and reactive oxygen species, and in such a cellular environment endoplasmic reticulum (ER) stress may also develop. 25,32 The link between ER stress and T1D mellitus has been suggested by several investigators. 33,34 A balance between ER protein load and folding capacity is needed for the proper folding of insulin within the ER.…”

Section: Multifactorial Etiology Of T1dmentioning

confidence: 97%

“…25 The initiating events in T1D pathogenesis that trigger the provision of b-cell antigens (the first described target antigen is insulin) to dendritic cells and presentation to T cells for their activation are yet to be elucidated. 26 As depicted in the Fig 2, proinflammatory cytokines, produced by infiltrating leukocytes and islet cells, including interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), and interferon g (IFN-g), play a central role in b-cell failure and the development of diabetes.…”

Section: Multifactorial Etiology Of T1dmentioning

confidence: 99%

“…Prolonged exposure to cytokines leads to a decreased capacity of b cells to produce and release insulin in response to secretagogues and, in the long term, destruction of the cells by apoptosis or necrosis. 25,28 T1D typically affects young children, with onset as early as 1 year of age; most cases are diagnosed before the patient is 18 years old. The autoimmune process starts even earlier, as evidenced by the presence of autoantibodies in serum against T1D-specific antigens.…”

Section: Multifactorial Etiology Of T1dmentioning

confidence: 99%

“…8 Post-GWAS fine mapping and functional characterization of T1D risk loci remain to be performed. 25 One of the most important challenges in post-GWAS functional characterization is to distinguish loss-of-function from gainof-function mutations and mechanisms that cause small changes in gene dosage with disease-specific phenotypic consequences. Many SNPs identified in GWASs are only tag SNPs that are in LD with the causative variant, in addition to being located in non-protein-coding regions of the genome, such as gene regulatory elements that do not directly affect protein structure.…”

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confidence: 99%

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Genetic and Epigenetic Factors in Etiology of Diabetes Mellitus Type 1

2013

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Diabetes mellitus type 1 (T1D) is a complex disease resulting from the interplay of genetic, epigenetic, and environmental factors. Recent progress in understanding the genetic basis of T1D has resulted in an increased recognition of childhood diabetes heterogeneity. After the initial success of family-based linkage analyses, which uncovered the strong linkage and association between HLA gene variants and T1D, genome-wide association studies performed with high-density single-nucleotide polymorphism genotyping platforms provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remains to be performed. T1D is one of the most heritable common diseases, and among autoimmune diseases it has the largest range of concordance rates in monozygotic twins. This fact, coupled with evidence of various epigenetic modifications of gene expression, provides convincing proof of the complex interplay between genetic and environmental factors. In T1D, epigenetic phenomena, such as DNA methylation, histone modifications, and microRNA dysregulation, have been associated with altered gene expression. Increasing epidemiologic and experimental evidence supports the role of genetic and epigenetic alterations in the etiopathology of diabetes. We discuss recent results related to the role of genetic and epigenetic factors involved in development of T1D. Pediatrics

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The transcription factor STAT6 plays a critical role in promoting beta cell viability and is depleted in islets of individuals with type 1 diabetes

et al. 2018

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Aims/hypothesisIn type 1 diabetes, selective beta cell loss occurs within the inflamed milieu of insulitic islets. This milieu is generated via the enhanced secretion of proinflammatory cytokines and by the loss of anti-inflammatory molecules such as IL-4 and IL-13. While the actions of proinflammatory cytokines have been well-studied in beta cells, the effects of their anti-inflammatory counterparts have received relatively little attention and we have addressed this.MethodsClonal beta cells, isolated human islets and pancreas sections from control individuals and those with type 1 diabetes were employed. Gene expression was measured using targeted gene arrays and by quantitative RT-PCR. Protein expression was monitored in cell extracts by western blotting and in tissue sections by immunocytochemistry. Target proteins were knocked down selectively with interference RNA.ResultsCytoprotection achieved with IL-4 and IL-13 is mediated by the early activation of signal transducer and activator of transcription 6 (STAT6) in beta cells, leading to the upregulation of anti-apoptotic proteins, including myeloid leukaemia-1 (MCL-1) and B cell lymphoma-extra large (BCLXL). We also report the induction of signal regulatory protein-α (SIRPα), and find that knockdown of SIRPα is associated with reduced beta cell viability. These anti-apoptotic proteins and their attendant cytoprotective effects are lost following siRNA-mediated knockdown of STAT6 in beta cells. Importantly, analysis of human pancreas sections revealed that STAT6 is markedly depleted in the beta cells of individuals with type 1 diabetes, implying the loss of cytoprotective responses.Conclusions/interpretationSelective loss of STAT6 may contribute to beta cell demise during the progression of type 1 diabetes.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4750-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Intracellular pathways of pancreatic β‐cell apoptosis in type 1 diabetes

Abstract: Our data indicate that different stimuli activate different initiator molecules in the Bcl-2-regulated pathway in β cells.

Cited by 21 publications

References 75 publications

Life and death of β cells in Type 1 diabetes: A comprehensive review

Life and death of β cells in Type 1 diabetes: A comprehensive review

Genetic and Epigenetic Factors in Etiology of Diabetes Mellitus Type 1

The transcription factor STAT6 plays a critical role in promoting beta cell viability and is depleted in islets of individuals with type 1 diabetes

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